1. Field of the Invention
This invention relates to improvements in curable compositions intended for use or placement in direct contact with a biological surface. More specifically, this invention discloses curable compositions with antimicrobial properties, together with methods for their use, which are useful for preventing microbial growth on one or more surfaces of the curable composition or within the curable composition or adjacent to the curable composition after curing and subsequent placement in contact with a biological surface.
2. Description of Related Art
Materials science has provided us with a plethora of compositions that can be transformed from an initial, malleable state to a final, non-malleable state, generally through the process of heating, the application of pressure, and/or the inducement of polymerization. Such compositions provide us with an array of materials that may be first molded into a desired shape, then subsequently induced to transform into a final, non-deformable shape identical (or nearly so) to the original molded shape. Such processes may employ heat or pressure (or both) to transform materials into a desired shape by manipulation of the physical properties of the material itself, or may alternatively utilize initiators and/or activators to begin a polymerization reaction throughout the shaped mass. Alternatively, a curing process may occur simply as a composition absorbs moisture from the surrounding environment. Such curing processes are seen in certain types of adhesives, such as urethanes-based caulks and denture adhesives.
The class of materials known as acrylics (which, for the purpose of this disclosure, shall mean compositions comprised wholly or in part of acrylate and/or methacrylate monomers and/or polymers, alone or in combination with each other and/or other unsaturated and/or saturated compounds) has gained acceptance as being particularly suited for the formation of prosthetics to be placed into contact with the body. In particular, acrylics have been used to form dental restorative materials, dentures, temporary crown and bridge materials, and artificial fingernails and toenails, as well as having been employed as adhesion promoters at the interface between a biological surface (herein defined as any external or internal surface of a living organism) and a prosthetic (in order to provide the extended wear time required of, for instance, a permanent dental restorative material). Curable acrylic compositions, when properly initiated or catalyzed, undergo free-radical addition reaction polymerization, which is exothermic (i.e. generates heats) in character.
As biological surfaces are invariably populated by a wide variety of microorganisms, inert objects (such as prosthetics or adhesives), when placed in contact with such surfaces are subject to surface colonization and, often, subsequent penetration by those same microorganisms. In addition, fluid infiltration at the interface between the biological and non-biological surfaces presents ideal conditions for the growth of microorganisms. In the absence of any protective mechanism to prevent such colonization, objects in contact with biological surfaces often become populated with a higher density of microorganisms than the original biological surface itself. Thus a prosthetic can become a breeding ground for potentially harmful microorganisms and subsequently itself become a source of infection to adjacent living tissue. For example, the occluded interface or margin between an inert object and a biological surface, due to the accumulation of moisture there (and often, the exclusion of oxygen, which results in an environment conducive to the growth of anaerobic microorganisms), can foster the development of microbial colonies in higher numbers than the same biological surface would have in a non-occluded state.
One example of this interfacial phenomenon is recurrent caries, which is though to be caused by the infiltration of microorganisms, in particular, those responsible for dental caries (tooth decay), into the interface margin between a dental restorative material (such as an amalgam or resin-based composite) and the natural tooth surface. In the process of preparing, placing and finishing a dental restoration, the marginal adaptation of the restorative material, in addition to the quality and strength of the bond between the restoration and the natural tooth surface, is of paramount importance to the restoration's longevity as a permanent prosthetic. If the adhesion of the restorative material is inadequate, or the shape of the restorative material is slightly non-conforming, oral fluids such as saliva, which constantly bathe the restoration, are able to infiltrate into the interface between the restorative material and the natural tooth. Microorganisms are carried along with the infiltrating fluids and may colonize the marginal space. The metabolites of certain microorganisms, such as Streptococcus mutans species, are potentially harmful to the natural tooth structure, and erosion of the tooth at the interface (recurrent caries and possible restoration failure) may occur over time.
Recurrent caries have been shown to be a major cause in the failure of dental restorations. The failure is thought to occur due to penetration of pathogenic organisms which as S. mutans into the tooth structure along the cavity wall through microleakage and/or accumulation of bacteria at the margins, or interface, between the restorative material and the tooth. The incidence of recurrent caries around restorations involving enamel can be reduced by using fluoride containing restorative materials. However, the amount of fluoride released has been shown to decrease significantly with time and thus cariostatic ability of these restorative materials over a long term remains unclear. To overcome this advantge, attempts have been made to supplement restorative materials with antimicrobial agents. Addition of chlorhexidine, a water soluble catonic antimicrobial agent to composite restorative materials ahve largely been unsuccesful because of the loss of efficacy and deterioration of physical properties. Attempts have also been made to add other types of antimicrobial agents to restorative materials. Recently, Imazato, et al. U.S. Pat. No. 5,733,949 incorporated methacryloyloxydodecylpyridinium bromide (MDPB) to experimental composites and showed that the attachment of S. mutans to surfaces of the restorative material was reduced. However, unlike chlorhexidine, no zone of inhibition was evident by the disk diffusion method, indicating that the agent is not released oris released at sub MIC levels. This finding suggests that MDPD has a potential disadvantage becasue it does not solve the problem of permeation of bacteria through the enamel-restoration interfaces and destroying bacteria in the cavity preparation.
The incidence of recurrent caries around restorations involving enamel can be reduced by using fluoride containing restorative materials. The purpose of the fluoride is to convert hydroxyapatite to fluorapatite, which is more resistance to acid attack. The major disadvantage with the use of fluoride is that it does not have significant antimicrobial activity and is easily washed away or diffuses away due to its high degree of solubility in the surrounding aqueous medium of the oral cavity.
To overcome one of the disadvantages indicated above, attempts have been made to add antimicrobial agents that are more effective against oral microorganisms than fluoride to dental materials, such as denture acrylics and denture soft liners. Chlorhexidine and its acetate or gluconate salts are water-soluble cationic antimicrobial agents capable of inhibiting or killing a wide variety of oral pathogens. However, incorporation of chlorhexidine salts in such compositions resulted in the rapid release of the highly water-soluble antimicrobial agent and subsequent impairment of the cured material's physical properties. See, for example, J. McCourtie, et al, Effect of Saliva and Serum on the Adherence of Candida Species to Chlorhexidine-treated Denture Acrylic in Journal of Medical Microbiology, Vol. 21, (1986), 209-213, in addition to M. Addy, In Vitro Studies into the Use of Denture Base and Soft Liner Materials as Carriers for Drugs in the Mouth in Journal of Oral Rehabilitation, Vol. 8, (1981), 131-142.
Attempts have also been made to add other types of antimicrobial agents to restorative materials. Recently, Imazato, et al. U.S. Pat. No. 5,733,949 incorporated methacryloyloxydodecylpyridinium bromide (MDPB) to experimental composites and showed that the attachment of S. mutans to surfaces of the restorative material was reduced. However, unlike chlorhexidine, no zone of inhibition was evident by the disc diffusion method, indicating that the agent is not released or is released at sub minimum inhibitory concentration (MIC) levels. This finding suggests that MDPB has a potential disadvantage because it does not solve the problem of permeation of bacteria through the enamel-restoration interfaces and destroying bacteria in the cavity preparation.
It has been shown that demineralization of surface enamel is caused by acid production from S. mutans and other cariogenic organisms, while demineralization along the cavity wall is caused by a combination of acid attack on outer enamel surfaces and additional acid attack through the gaps or microleakage between the cavity wall and the restoration. Both types of acid attack can be prevented by cariostatic agents deposited on the outer surfaces, at the cavity walls and in the areas of microleakage. Hence, the presence of cariostatic agents or antimicrobial agents may reduce or eliminate caries formation via reducing the solubility of enamel or inhibition of bacterial activity.
Attempts have also been made to add water-insoluble antimicrobial agents to dental materials for the purpose of inhibiting surface growth. See J. Osaka Univ. Dent. Sch., vol. 35, pp. 5-11, 1995. In JP Patent Application No. 3-118309, triclosan was added to the monomer of a light-curable composite material and the material subsequently cured with a curing light. The release of the triclosan into the surrounding medium was extremely low (0.02 micrograms/ml) for most of the compositions tested. As a result, the investigators did not observe the reduction of bacteria around disks made from the various triclosan-impregnated compositions until the triclosan concentration was well in excess of 1 percent by weight, namely 4% by weight. Only at 4 percent by weight triclosan, was there a slight (&lt;1 mm) zone of bacterial inhibition around the disk prepared from a light-cured composite restorative material. The cured composition was ineffective at levels below 4% triclosan in inhibiting or destroying bacteria in the medium surrounding (i.e., not in direct contact with) the restoration.
Dental restorative materials, especially resin-based composites (which are generally composed of a fluid matrix carrier based on modified acrylic monomers and/or polymers, together with a dispersed inorganic phase composed of glass, silica, and other finely divided materials), are able to support the growth of microorganisms on surfaces exposed to the oral environment. Such surfaces are seen to accumulate plaque and tartar to a degree often greater than an exposed natural tooth surface. Again, such accumulation may have an impact on the health of adjacent natural hard and soft tissue surfaces, for instance, the irritation of gingival tissues adjacent to a heavily colonized restorative surface.
Another example of this interfacial phenomenon occurs in the artificial fingernail art. Artificial fingernails are often formed by dipping an artist's brush into a liquid acrylic monomer, which contains a polymerization initiator (typically a tertiary amine such as dimethyl-p-toluidine). The wetted brush is then contacted with a reservoir containing an acrylic polymer, which also contains a polymerization initiator (such as benzoyl peroxide). The resulting slurry of liquid and powder that adheres to the brush is transferred to the natural fingernail surface and the polymerization initiators interact to cause polymerization of the slurry into a hard mass within a period of about three to seven minutes.
Although the natural fingernail surface is typically prepared in such a fashion as to attempt to assure the exclusion of microorganisms prior to placement of the artificial fingernail slurry, oftentimes the preparative procedure results in a natural nail surface that is less than sterile. Even if sterile conditions on the natural fingernail surface were achievable in practice (which they are not), an insufficient bond strength between the polymerized artificial fingernail and the natural nail surface will result in the potential for fluid infiltration into the interfacial space created by a partial separation. Such fluid infiltration can result, as in the dental restorative example above, in the colonization of the natural fingernail/artificial fingernail interface by externally-derived microorganisms (such as Pseudomonas aeruginosa, which has been identified as the most common source of nail infections).
Another example of the problems associated with surface colonization of acrylic prosthetics is found in dentures. The extended wear time achieved by more modern denture adhesive formulations has resulted in a longer residence time for dentures, which are based on acrylic polymers. The preparation of a denture is a process well known in the art and is more fully described in references such as Phillip's Science of Dental Materials, K. J. Anusavice, ed. 10.sup.th Edition, 1996 (W. B. Saunders & Co). A typical denture is prepared by taking an impression of a patient's edentulous arch, creating a dental cast from the impression, and then creating a resin record base on the casting. Subsequently, wax is added to the record base and the artificial teeth are positioned in the wax. A pressure container, called a "flask" is chosen and the completed tooth arrangement is encased in an investment medium. The flask is then opened and the wax eliminated. The denture base material is then introduced into the mold cavity and the complete assembly polymerized by either a combination of heat and pressure, or alternatively through a chemical curing process. The flask is opened and the finished denture removed.
Extended denture retention time has resulted in a longer period during which oral microorganisms can utilize the denture adhesive composition and then enter the surface of the denture itself as a growth medium. Growth of oral microorganisms within denture adhesive compositions and on the surfaces of dentures have been identified as causes of oral malodor associated with denture use. Microorganism growth on the denture can be promulgated by the adjacent growth in the denture adhesive. Denture-induced stomatitis (DIS) and inflammatory papillary hyperplasia (IPH) are conditions that are known to result from dentures with microorganism-contaminated surfaces (see, for example, E. Budtz-Jorgensen, et al, in Quantitative Relationship between Yeast and Bacteria in Denture-Induced Stomatitis, Scandinavian Journal of Dental Research, Vol 91(2) (1983), 134-142).
In order to provide additional comfort to wearers of dentures, soft relining materials are often employed to facilitate better adaptation of the attachment surface (generally in the region of the palate) and to provide a "cushion" between the hard denture surface and the point of attachment in the oral cavity. Soft reliners are typically self-curing (autopolymerizing) acrylic materials that utilize acrylic monomers and/or polymers with a relatively low glass transition temperature (T.sub.g). Alternatively, plasticizers such as dibutyl phthalate are used to provide elasticity to the cured soft reliner composition. The high flexibility and softness of such materials results in a greater degree of porosity, thus increasing the likelihood of microbial colonization. In particular, it has been shown that soft reliner materials support the growth of Candida albicans, a fungal organism thought to be associated with denture stomatitis. Previous attempts to limit the growth of microorganisms in soft reliner materials have been made through the inclusion of water-soluble antimicrobial agents such as zinc undecylenate and undecylenic acid.
The durability of the antimicrobial effect in prior art compositions containing one or more water-soluble antimicrobial agents is relatively poor, presumably due to the rapid rate at which the agent is released from the material into the surrounding aqueous medium. More often than not, the presence of a water-soluble molecule within a cured composition will contribute to the deterioration of said composition's physical properties; it is presumed that the voids left in a cured composition's polymeric structure by the solubilized antimicrobial can render the material unsuitable or its intended purpose.
There is thus a need for improved compositions and methods that address the problems associated with acrylic prosthetics and adhesives placed in contact with a biological surface.
In particular, there is a need for improved compositions and methods for their use that prevent the growth of microorganisms at the interface between a biological surface and a non-biological surface.
Furthermore, there is a need for improved curable compositions and methods for their use that can inhibit or kill microorganisms in the surrounding medium in which they are placed.